Effectiveness of couple education and counseling on knowledge, attitude and uptake of cervical cancer screening service among women of child bearing age in Southern Ethiopia: A cluster randomized trial protocol

Background Cervical cancer occurred nearly in 570 000 women and 311 000 women died from the disease worldwide in 2018. Of the new cases diagnosed globally in 2012, approximately 85% of the burden took place in low- and middle-income countries. Human Papilloma virus is the necessary cause for the development of cervical cancer and the majority of these infections resolves naturally but progress to precancerous lesions whenever there is persistence and delay in treatment. Majority of the cervical cancer cases, over 80% in sub-Saharan Africa including Ethiopia, have been detected at a late stage mainly due to poor early preventive measures. Therefore, utilization of early preventive measures could increase timely detection and treatment of precancerous changes and significantly reduce morbidity & mortality due to advanced disease. Methods In this interventional study we will randomly assign 16 clusters (kebeles) in to the intervention and the control arm using block randomization. The study will employ a cluster randomized controlled trial. Women are eligible to participate in this study when they satisfy certain eligibility criteria; being in the age range of 30–49 years, no history of hysterectomy, did not receive cervical cancer or pre-cancer treatment and non-pregnant. Home based couple education and counseling will be provided to the eligible participants within the intervention group, while the control group receives standard of care. Base line and end line surveys will be completed by interviewing 288 eligible women to evaluate the effect of couple education and counseling on the knowledge, attitude and cervical cancer screening uptake. Generally the intervention lasts for six months. The results of baseline & end line surveys will be compared between the groups to determine the effectiveness of the intervention. Blinding is not possible due to the clustering of the trial arms. Discussion Findings of the study will inform the regional or national scale up of the intervention modality to achieve the screening targets set by the Ethiopian government and world health organization. Trial registration PACTR, PACTR202108529472385. Registered on 05 August 2021, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=16037


Background
Cervical cancer occurred nearly in 570 000 women and 311 000 women died from the disease worldwide in 2018. Of the new cases diagnosed globally in 2012, approximately 85% of the burden took place in low-and middle-income countries. Human Papilloma virus is the necessary cause for the development of cervical cancer and the majority of these infections resolves naturally but progress to precancerous lesions whenever there is persistence and delay in treatment. Majority of the cervical cancer cases, over 80% in sub-Saharan Africa including Ethiopia, have been detected at a late stage mainly due to poor early preventive measures. Therefore, utilization of early preventive measures could increase timely detection and treatment of precancerous changes and significantly reduce morbidity & mortality due to advanced disease.

Methods
In this interventional study we will randomly assign 16 clusters (kebeles) in to the intervention and the control arm using block randomization. The study employed a cluster randomized controlled trial. Women are eligible to participate in this study when they satisfy certain eligibility criteria; being in the age range of 30-49 years, no history of hysterectomy, did not receive cervical cancer or pre-cancer treatment and nonpregnant. Home based couple education and counseling will be provided to the eligible participants within the intervention group, while the control group receives standard of care. Base line and end line surveys will be completed by interviewing 288 eligible women to evaluate the effect of couple education and counseling on the knowledge, attitude and cervical cancer screening uptake. Generally the intervention lasts for six months. The results of baseline & end line surveys will be compared between the groups to determine the effectiveness of the intervention. Blinding is not possible due to the clustering of the trial arms.
Discussion: Findings of the study will inform the regional or national scale up of the intervention modality to achieve the screening targets set by the Ethiopian government and world health organization.    naturally but progress to precancerous lesions whenever there is persistence and delay in 20 treatment. Majority of the cervical cancer cases, over 80% in sub-Saharan Africa including 21 Ethiopia, have been detected at a late stage mainly due to poor early preventive measures.

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Therefore, utilization of early preventive measures could increase timely detection and treatment 23 of precancerous changes and significantly reduce morbidity & mortality due to advanced disease.

Methods 25
In this interventional study we will randomly assign 16 clusters (kebeles) in to the intervention 26 and the control arm using block randomization. The study employed a cluster randomized 27 controlled trial. Women are eligible to participate in this study when they satisfy certain   This study is a two arm parallel cluster randomized trial that will be conducted in the Southern 117 people regional state of Ethiopia.
118 Study setting 119 The geographic location for our study is Kembata Tembaro and Hadiya zones which are located 120 in the Southern Nations Nationalities and Peoples' Regional State. The total number of age  Participants' eligibility 136 The study participants are women of child bearing age who are eligible for cervical cancer 137 screening according to the Ethiopian national cervical cancer prevention and control guideline 138 (14). Accordingly women aged 30-49 years are targets for cervical cancer screening program and 139 our research will be carried out within this program framework. Women should also satisfy the 140 requirements of legal residency within their respective living quarters for at least six months, 141 have not had received the screening services within the last 5 years, non-pregnant, beyond three to intervention and control groups using block randomization technique. Census or health post 149 records will be used to identify all the eligible women for cervical pre-cancer screening in the 150 selected clusters and sampling frame will subsequently be created. Then, simple random 151 sampling technique will be used to select study participants from each cluster for each arm. We 152 will select an equal number of participants from each selected cluster.

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Those women who consent to participate in the study will be included and requested to sign an  The clusters or kebeles are the units of randomization in our study. Initially, sixteen non-adjacent 161 clusters, eight from each district, were identified from the two study districts. We stratified the 162 clusters based on the study districts and created separate list of eight clusters alphabetically for 163 each district. The stratification was done to evenly distribute any known and unknown district 164 level confounders across the study arms. Each cluster was assigned a unique cluster code. Then, 165 the statistician assigned the eight clusters in to two blocks of size 4 according to the order they 166 appeared alphabetically. The statistician randomly selected the randomization sequence of 167 clusters for each block using the sealed lots of the six possible permutations within the block.

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The clusters in each block were randomly assigned to intervention and control arms according to 169 the randomization sequence evident by the selected permutation within in the block for the 170 stratum. We repeated the same process for blocks of clusters in the other stratum. Consequently, 171 four clusters were obtained from each district which formed eight clusters to the intervention arm 172 and eight clusters to the control arm maintaining 1:1 random allocation ratio.

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The statistician was made unaware of the actual study arms to mask the knowledge about which 174 group will receive the intervention and which group will receive the usual care. This was 175 achieved by representing the study arms and clusters by confidential codes. Health extension 176 workers will carry out identification of eligible participants' for the study and subsequent 177 intervention administration activities. Assessors will also be made blind to the nature of clusters 178 with respect to intervention administration.

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A follow up visit will be made to each woman one month after the initial visit with the objectives 223 to re-emphasize important points of the material and make encouragement for screening. During 224 this visit both the woman and her husband together will receive key information on cervical 225 cancer and the importance of its screening. The husband will also be counseled on the 226 importance and the way how the woman receives his support and encouragement to get screened 227 for cervical cancer. Additionally any misconceptions related with the information will be 228 corrected and barriers to screening will be addressed during this visit. Repeated follow up visits 229 will be made in a case of absence of the couples. 230 Finally, the second follow up visit, which is the last visit of the proposed intervention modality, 231 will be made one month after the first follow up visit to convey key messages about cervical 232 cancer and its screening and address any unresolved concerns related to cervical cancer and its 233 screening. Also, a formal letter of invitation will be granted during this visit for free screening 234 services available in the nearby health facility. During all the visits eligible women will be asked 235 key questions at the end of education and counseling session to check women's comprehension.

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Also screening preparedness plan will be continuously negotiated with the woman at each visit 237 as an encouragement to get screened for cervical cancer. control group will receive the usual standard of care but will be exposed to the same intervention 246 after the trial period through the routine services delivery schemes [ figure 2]. 247 Implementation of screening service 248 Those women who visit the screening facilities will receive the service according to the national 249 guideline. Women will be provided with the specific information how they will access the 250 service delivery location and whom they will contact within the health facility. Accordingly 251 women who come from the study clusters for screening will be linked to the administrative 252 procedures of the health facility to receive the screening service. A trained health professional 253 will undergo assessment & counseling and conduct the screening procedure using visual 254 inspection techniques according to the guideline. Any woman with positive precancerous 255 screening results will receive treatment immediately after the results become available on the 256 same day visit and be counseled to receive a follow up screening after one year. Those women 257 who are tested negative will be counseled to receive a regular screening service after five years.

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All women who receive the screening will be registered on the format prepared for study 259 purpose. compliance to the proposed intervention requirements will be considered during analysis as a 267 dose response function. Therefore, compliance checklist will be used to track the level of 268 women's compliance to our proposed intervention package to account for during data analysis.  The primary outcome of this study is the completion of cervical cancer screening test within 6 273 months of the baseline assessment. Participants will be interviewed using the survey difference in the screening proportions between intervention and control arms will be calculated.

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Finally, the effectiveness of the intervention will be measured as a difference of the differences 278 in the screening uptake between the study arms.

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Secondary outcomes 280 We will also assess the progress of participants' knowledge and attitude by measuring their 281 knowledge and attitude at baseline and end line. The effect of the intervention on participants' 282 knowledge and attitude will be determined and compared between the study arms.  Table 2 Participants' timeline of enrolment, intervention and assessment Sample size 286 We identified current cervical cancer screening proportions from existing literatures to be 15.5% 287 among age eligible women (18) for the control arm. We will expect an absolute difference of 288 20% increase in screening proportions between the arms with the power of 80% and 5% 289 significance level for one-tailed test which gives the expected proportions of screening to be 290 35.5% for the intervention arm. We also considered the design effect of 2 to adjust for the loss of 291 variability due to clustering and 5% compensation for incomplete and non-response rates that 292 would happen during data collection. Consequently, we arrived at a total of 288 study 293 participants. We used Gpower software to determine our sample size. The required number of 294 clusters we determined for the study is sixteen clusters.

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Sampling procedure 296 Sixteen clusters (kebeles) will be selected from the two study districts where cervical cancer 297 screening service is currently available. Sixteen clusters are taken based on the recommendation 298 that taking fewer subjects from many clusters give better representation of the sample than taking 299 many participants from fewer clusters. The clusters will be randomly assigned in to intervention 300 and control groups. Census will be carried out in the selected Kebeles to identify women who are 301 eligible for screening and to create sampling frame. Then, simple random sampling technique 302 will be performed to select study participants in each arm. We will select equal number of 303 participants from each cluster which consequently leads to selection of 18 participants per 304 cluster. The same sample of participants will be used at the end of the intervention phase, six 305 months later, to measure outcome variables [ figure 1].

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Data will be collected using structured questionnaire designed for meeting the specific research 308 purpose. The tool has been developed based on the research objectives from relevant literature 309 sources. The data collection instrument will be pretested to check for its clarity, logical sequence, 310 cultural appropriateness etc. and appropriate modification will be made accordingly. Participants 311 will be interviewed to complete baseline survey after randomization of the clusters and end line 312 survey at the end of the intervention period in six months. Participants will be measured for 313 socio-demographic characteristics, knowledge, attitudes, and cervical cancer screening uptake.

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Data will be collected through face to face interview technique contacting each woman at her 315 residential home. Data collectors will go to each selected woman's home physically by carrying 316 all the data collection tools and communicate verbally with the local language to get the required 317 information. Two different teams will be assigned for the intervention administration and data 318 collection for the purpose of masking the intervention from data collectors. Both the baseline and 319 end line data will be collected by the same individuals to ease the data gathering process.

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Confidentiality of the data 321 The information we will obtain from the participants will be kept confidential and used only for 322 the purpose of the study. No personal identifiers will be recorded on the information and data 323 recording sheet and only codes will be employed. The completed data checklists will be kept in a 324 secure manner until it will be officially discarded.

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Data management 326 Specific cluster and individual codes will be assigned for each of the completed questionnaire.

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The data will be entered using Epi info version 7.2.4.0. The data will be edited and transported to 328 either SPSS or STATA to carry out the desired statistical analysis. categorical variables and independent sample t-tests for continuous variables. A one-sided P 335 value of 0.05 will be used to determine statistical significance.

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After the end line survey, proportions of women screened during the trial period will be 337 calculated. We will use paired sample t-test to test knowledge about cervical cancer and cervical 338 cancer screening, within the intervention group by comparing the before and after intervention 339 scores. A similar analysis will be done for the control group to compare before and after 340 intervention scores. Then we will employ the independent-sample t-test to determine the effect of 341 the intervention on knowledge and attitude by comparing participants' scores on knowledge and 342 attitude about cervical cancer and its screening, between the two groups.

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Finally, we will use Generalized Estimating Equation analysis technique to test the independent 344 effect of the intervention on the uptake of cervical pre-cancer screening services. Intention to 345 treat approach will be employed to analyze the data. The findings of this trial will be disseminated to relevant stake holders in the local community.

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The findings will also be communicated to the scientific community through publication of the 354 results in the peer reviewed journals. protocol will be communicated to the IRB for approval. Each participant will sign consent before 376 data collection by the help of the data collectors using the consent format prepared for the 377 research purpose and its copy will be issued for the participant. 379 Not applicable.

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Availability of data and materials 381 The datasets generated during the study will be made available through the corresponding author 382 upon justified official requests.

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Competing interests 384 The authors declare that they have no competing interests 385

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This research will be carried out by financial support from Jimma University. Jimma University 387 had no role over the design, data collection, management and analysis, report writing, 388 interpretation and the decision to submit the report for publication process. team. The information obtained in this study will be used only for research purposes. The 463 information you will provide is helpful to achieve the intended objectives of the study so that you 464 and your community will benefit from. Any information obtained will be kept strictly 465 confidential and will not be exposed to any other body. No personal identifiers will be attached